Review
Mechanisms of action for the medium-chain triglyceride
Lancet Neurol 2018; 17: 84–93
*Contributed equally
Centre for Biomedical Sciences,
School of Biological Sciences,
Royal Holloway University of
London, Egham, UK
(K Augustin BSc,
Prof R S B Williams PhD); and
UCL Great Ormond Street
Institute of Child Health
(A Khabbush MSc, S Eaton PhD,
M Orford PhD,
Prof S J R Heales PhD),
Department of Clinical and
Experimental Epilepsy, UCL
Institute of Neurology
(S Williams PhD,
Prof M C Walker PhD), and
Neurosciences Unit, UCL
Institute of Child Health
(Prof J H Cross PhD), University
College London, London, UK
Correspondence to:
Prof Robin S B Williams, Centre
for Biomedical Sciences, School
of Biological Sciences, Royal
Holloway University of London,
Egham, TW20 OEX, UK
Robin.Williams@rhul.ac.uk
84 www.thelancet.com/neurology Vol 17 January 2018
ketogenic diet in neurological and metabolic disorders
Katrin Augustin, Aziza Khabbush, Sophie Williams, Simon Eaton, Michael Orford, J Helen Cross, Simon J R Heales*, Matthew C Walker*,
Robin S B Williams*
High-fat, low-carbohydrate diets, known as ketogenic diets, have been used as a non-pharmacological treatment for
refractory epilepsy. A key mechanism of this treatment is thought to be the generation of ketones, which provide
brain cells (neurons and astrocytes) with an energy source that is more efficient than glucose, resulting in beneficial
downstream metabolic changes, such as increasing adenosine levels, which might have effects on seizure control.
However, some studies have challenged the central role of ketones because medium-chain fatty acids, which are part
of a commonly used variation of the diet (the medium-chain triglyceride ketogenic diet), have been shown to directly
inhibit AMPA receptors (glutamate receptors), and to change cell energetics through mitochondrial biogenesis.
Through these mechanisms, medium-chain fatty acids rather than ketones are likely to block seizure onset and raise
seizure threshold. The mechanisms underlying the ketogenic diet might also have roles in other disorders, such as
preventing neurodegeneration in Alzheimer’s disease, the proliferation and spread of cancer, and insulin resistance
in type 2 diabetes. Analysing medium-chain fatty acids in future ketogenic diet studies will provide further insights
into their importance in modified forms of the diet. Moreover, the results of these studies could facilitate the
development of new pharmacological and dietary therapies for epilepsy and other disorders.
Introduction The MCT ketogenic diet is used worldwide to treat
The ketogenic diet is a high-fat, low-carbohydrate diet that drug-resistant epilepsy, mainly in children,1 but also in
was developed as a treatment for epilepsy.1 The diet aims adults.3,4 Both the classic and MCT ketogenic diets have
to mimic the metabolic profile of fasting by reducing garnered increased interest as potential treatments for
blood glucose concentration and increasing blood ketone other diet-sensitive disorders, including Alzheimer’s
concentration because starvation has long been reported disease,5–7 cancer,8–12 and diabetes.13,14 As with epilepsy, the
to reduce the frequency of seizures. Under normal dietary main therapeutic mechanism was assumed to occur
conditions, the brain uses glucose as an energy source; by through replacing carbohydrates with ketones as an
contrast, during fasting conditions, ketones are used as energy source.15 However, despite the efficacy of the
the main energy source. Hence, starvation (associated ketogenic diet in controlling seizures in patients with
with seizure control) induces ketone generation, which epilepsy, several studies have shown a poor correlation
might be the therapeutic mechanism of action. Despite between blood plasma ketone concentrations and seizure
the common use of the ketogenic diet to treat epilepsy, the control,16,17 and ketones do not acutely block seizure
mechanisms underlying its efficacy have remained activity in an animal model.18 An additional study19 has
unclear. However, advances in our understanding of the shown seizure control in the absence of ketosis. These
mechanisms of action of medium-chain fatty acids have observations challenge the view that ketones alone have a
resulted in a paradigm shift in the hypothesis behind the role in seizure control and raise the question of the roles
mechanisms of the diet, away from ketones as a of other components of the diet, particularly fats that are
therapeutic mechanism and focusing on fatty acids provided at high levels in the diet. Additionally, several
instead, paving the way for novel dietary and drug studies20–23 have indicated that medium-chain fatty acids
therapies for epilepsy and other disorders. provided in the MCT ketogenic diet can have a direct
There are two forms of the ketogenic diet. The so-called action on seizure activity and mitochondrial function.
classic ketogenic diet provides 60–80% of dietary energy The aim of this Review is to describe the most recent
through long-chain fats, which have 16–20 carbon advances in our understanding of the mechanisms of
atoms.2 This diet is particularly stringent, with very low action of the MCT ketogenic diet in relation to epilepsy
carbohydrate content, and consequently, it is difficult to and to other disorders.
maintain. As such, an alternative medium-chain
triglyceride (MCT) ketogenic diet was developed,2 in Metabolism of medium-chain triglycerides
which fats are provided though triglycerides comprising Dietary triglycerides (provided as a supplement in the
about 60% octanoic acid (an eight-carbon fatty acid) and MCT ketogenic diet) are broken down in the
about 40% decanoic acid (a ten-carbon fatty acid). By gastrointestinal tract by lipases that preferentially
contrast with the classic ketogenic diet, only about 45% of hydrolyse medium-chain esters over long-chain esters
dietary energy is provided by these medium-chain fats (figure 1).24 MCTs are hydrolysed to medium-chain fatty
(allowing a larger carbohydrate component),2 and the acids (fatty acids with six to 12 carbon atoms), which are
more rapid metabolism of the shorter fatty acids results then absorbed directly through the gut wall and
in more efficient generation of ketones. transferred to the liver, where the medium-chain fatty
 Review

acids (eg, decanoic acid and octanoic acid) are rapidly
metabolised through β-oxidation. Metabolism of these
fatty acids mainly results in the generation of three major
ketones, β-hydroxybutyrate, acetoacetate, and acetone
(collectively called ketone bodies).24 These ketones and
any fats that escape metabolism are distributed through
the blood in the circulatory system. The brain is thought
to be primarily dependent on glucose as an energy source,
and secondarily on hepatically derived ketone bodies.
However, medium-chain fatty acids are able to cross the
blood–brain barrier,25,26 reaching brain concentrations that
are more than 50% of those of fatty acids in plasma25 and
providing an alternative energy source for brain cells
(neurons and astrocytes). Evidence suggests that
medium-chain fatty acids have direct and differing effects
on brain cell energy metabolism. Octanoic acid seems to
undergo β-oxidation in astrocytes more easily than
decanoic acid and consequently more readily produces
ketones, whereas decanoic acid preferentially stimulates
glycolysis, producing lactate,27 which brain cells are able

Medium-chain triglycerides Medium-chain fatty acids Ketone bodies

O OH O
O Decanoic acid β-hydroxybutyrate
O O OH
HO O O
Acetoacetate
O O O Octanoic acid OH
O
O HO Acetone

Astrocyte

1 5
O
O O
Astrocyte
O O
extensions
O

O
HO
O OH O
OH
O O
OH Neuron

3
2
HO
HO
O OH
OH

O
OO
OO
O
O
HO

Figure 1: Breakdown and circulation of dietary medium-chain triglycerides

(1) Medium-chain triglycerides (containing decanoic acid and octanoic acid) are consumed as part of the medium-chain triglyceride ketogenic diet. (2) Medium-chain
fatty acids (decanoic acid and octanoic acid) are liberated from the triglycerides in the intestine and then transferred to the liver, where (3) most of these
medium-chain fatty acids are broken down to three ketone bodies (β-hydroxybutyrate, acetoacetate, and acetone). (4) Both free fatty acids and ketones are
transported to the brain through blood circulation. (5) Fatty acids and ketones are transported across the blood–brain barrier, where they are available as a source of
energy to brain cells.

www.thelancet.com/neurology Vol 17 January 2018 85

 Review
to use as an energy source. Decanoic acid could promote
the astrocyte–neuron lactate shuttle, which has been
proposed to be the main energy source for brain cells;
however, the importance of this shuttle as an energy
source has been challenged by multiple lines of evidence,
in which it was shown that oxidative glucose metabolism
is underestimated and ATP generated from lactate is
overestimated in most conditions.28 Similarly, octanoic
acid is preferentially oxidised (over decanoic acid) in brain
cells,29 suggesting a key metabolic role of neurons in the
differential regulation of medium-chain fatty acid
concentrations in the brain.
The medium-chain triglyceride ketogenic diet
and epilepsy
Ketones and seizure control
Under normal dietary conditions, ketone bodies are found
in blood plasma at very low concentrations, but their
concentration increases under fasting conditions up to a
total of 9 mmol/L and they can cross the blood–brain
barrier via monocarboxylate transporters.30 Under fasting
conditions, ketones can provide the energy source for
cells, and have been thought to be the key mechanism of
action of the ketogenic diet in controlling seizure
frequency in patients with epilepsy.15,31 Patients with
mutations of the glucose transporter GLUT1, which has a
crucial role in transporting glucose from the circulatory
system to the brain, respond well to both classic and MCT
ketogenic diets because ketones are thought to replace the
energy supply normally provided by glucose.32 Glucose
supple­ mentation was found to diminish the anti­
convulsant effects of the ketogenic diet in a mouse model
of epilepsy,33 suggesting that both fat administration and
carbohydrate restriction in the ketogenic diet might be
important in seizure control. Ketone bodies probably
affect aminoacid metabolism, either directly as substrates
or indirectly, resulting in changes to GABA and glutamate
concen­trations.34 But do ketones have any direct or indirect
effects on synaptic transmission or intrinsic neuronal
excitability? The ketones β-hydroxybutyrate and aceto­
acetate do not affect ionotropic GABA(A) receptors or
glutamatergic (AMPA and NMDA) receptors at
therapeutically relevant concentrations,35 while the
ketones acetone and β-hydroxybutyrate only affect
GABA(A) receptors and glycine receptors at very high
concentrations (>100 mmol/L).36 Nevertheless, ketones
have been suggested to be able to compete with chloride at
the vesicular glutamate transporter, decreasing vesicular
glutamate content and consequently glutamatergic
transmission.37 Additionally, high concentrations of aceto­
acetate (>10 mmol/L) have been shown to inhibit voltage-
dependent calcium channels in pyramidal cells of the
hippocampus, resulting in reduced excitability in the
hippocampus.38 However, in rat models, ketones at high
concentrations (≤10 mmol/L) have no direct effects on
seizure-like activity induced in hippocampal slices by
applying the GABA(A)-receptor antagonist pentetrazol,18
86 www.thelancet.com/neurology Vol 17 January 2018
or exposing them to low external magnesium. Despite a
possible effect on glutamatergic transmission, the
evidence, therefore, does not support a direct action of
ketones on seizure activity.
However, ketones can have indirect effects on neuronal
and network excitability, and anticonvulsant effects have
been shown in some rodent models of seizure.39–41
Switching from glucose to ketones as an energy source
has also been suggested to result in a hyperpolarisation of
neurons and a reduction in neuronal excitability. One
indirect mechanism could be the reduction in ATP
production from glucose oxidation, opening ATP-sensitive
potassium channels;42 in particular, the ketone
β-hydroxybutyrate has been proposed to modify seizures
through this pathway in addition to GABA(B) receptor
signalling in a model of seizures in Drosophila.43 Other
possible indirect mechan­isms include inhibition of the
mitochondrial permeability transition pore, which has
been implicated in mito­ chondrial dysfunction and
neuronal death, and inhibition of adenosine kinase,
thereby increasing adenosine levels and activating the
inhibitory adenosine A1 receptors.39,40 Moreover, ketones
have been implicated in epigenetic effects that could be
disease modifying in patients with chronic epilepsy,
possibly through an action on adenosine metabolism.44,45
Overall, the evidence that ketones can have an effect on
seizure control is mixed, and this reduced seizure activity
probably occurs through indirect metabolic effects.
Medium-chain fatty acids as a direct mechanism for
seizure control
Research on use of MCTs in the ketogenic diet has
provided important insights into the roles of fatty acids in
seizure control. The efficacy of decanoic acid in seizure
control has been shown in experiments in rats in which
seizure-like activity was induced in hippocampal slices,
either with pentetrazol or with perfusion of artificial CSF
containing no magnesium.18 Importantly, in these
experiments, decanoic acid blocked seizure-like activity
within 30 min of application in both models of seizure-
activity induction, while ketones (β-hydroxybutyrate and
acetone) did not.18 Decanoic acid also increased seizure
thresholds in animal models of acute seizures using both
the 6 Hz stimulation test (a model of drug-resistant
seizures)46 and the maximal electroshock test (a model of
tonic–clonic seizures),25 although it was not effective in
blocking pentetrazol-induced seizures in vivo (proposed
to be a model of absence seizures). These experiments
support a direct role of decanoic acid in in-vivo seizure
control.
An important step in understanding the role of
decanoic acid in seizure control was the discovery that
decanoic acid can directly and selectively inhibit AMPA
receptors in animal models (figure 2).18 These receptors
are key components in the generation of seizures47 and
can be blocked by micromolar concentrations of decanoic
acid.18 The mean concentration of decanoic acid in blood

from patients with epilepsy who receive the MCT
ketogenic diet is around 157 µM, whereas no decanoic
acid was found in individuals not on the diet.48 An animal
study25 showed that decanoic acid rapidly and easily
crossed the blood–brain barrier after ingestion. It is
therefore likely that, in patients with epilepsy on the
MCT ketogenic diet, decanoic acid would reach sufficient
concentrations in the brain to reduce excitation and
thereby provide reduced seizure frequency. This decanoic
acid-dependent AMPA receptor inhibition shows en­
hanced inhibition during synaptic activation (when
neurons are depolarised) and is non-competitive to
glutamate;18 it is also likely to be receptor-isoform specific,
and thus might provide a strong basis for therapeutic
efficacy. Direct inhibition of AMPA-receptor activity has
been well established as an effective therapeutic
mechanism in focal seizures and generalised tonic–clonic
seizures, and the antiepileptic drug perampanel acts
directly on AMPA receptors but at a different site from
decanoic acid.49,50 As such, the effects of decanoic acid
seen in animal models are likely to be a direct result of
AMPA-receptor inhibition.
Octanoic acid is the most abundant fatty acid when the
MCT ketogenic diet is supplied, and is found in concen­
trations of about 310 μM in the plasma of patients with
epilepsy.48 Animal studies have investigated its role in
seizure control. In one series of experiments, acute oral
dosing with increasing levels of octanoic acid increased
the threshold for induction of myoclonic and clonic
convulsions in rats.26 In a mouse model using 6 Hz
stimulation to induce seizures, octanoic acid
administered orally (by gastric gavage) also significantly
increased the seizure threshold in an adenosine-receptor-
dependent manner under reduced blood glucose
concentrations.51 However, in the same seizure model,
this thera­ peutic effect was not seen in animals that
received dietary octanoic acid-containing triglycerides
when glucose levels were not controlled.46 Octanoic acid
had no inhibitory activity on AMPA receptors at
concentrations found in patients with epilepsy on the
MCT ketogenic diet,18 suggesting that the potential
anti-seizure effect was more likely to occur through
indirect effects on adenosine receptors. However, in
animal studies, novel branched octanoic acid derivatives,
such as 5-methyloctanoic acid, provide both in-vitro and
in-vivo seizure control and AMPA-receptor inhibition.18,20,21
Medium-chain fatty acids as an indirect mechanism for
seizure control
An alternative mechanism for the effect of the MCT
ketogenic diet on epilepsy arises from beneficial effects
on brain energy metabolism. The diet causes alterations
in glycolysis or mitochondrial function, or both, after
which increasing ATP availability leads to an increase in
seizure threshold.52 Although long-chain fatty acids can
uncouple mitochondria, potentially decreasing ATP
production and lowering the seizure threshold (although
www.thelancet.com/neurology Vol 17 January 2018 87
Review
NH₂
Amino terminal
domain
Ligand-binding site Glutamate
Ligand-binding
domain
Extracellular S1-M1 S2-M4
M1 M3 M4
M2
Cytoplasmic
COOH
Figure 2: Schematic representation of binding sites on AMPA receptors
AMPA receptors occur as heterotetramers. Individual subunits comprise a large
extracellular amino (NH2) terminal domain and a glutamate ligand-binding
domain, three transmembrane domains (M1, M3, and M4), and one re-entry
loop (M2). The proposed site for decanoic acid on the M3 domain (red box) is
distinct to those of perampanel at the linker regions (S1-M1 and S2-M4; green
boxes) in the M1 and M4 domains. The carboxy terminal (COOH) resides in the
cytoplasmic domain.
mitochondrial uncoupling can also have a paradoxical
neuroprotective effect),53–55 medium-chain fatty acids are
much less likely to have a physiological role as
uncouplers.24 Clinical studies56,57 into the effects of
ketogenic diets in patients with mitochondrial disorders
report substantial improve­ments in seizure control. This
effect might be partly due to an action of decanoic acid
on the peroxisomal proliferator-activated receptor γ
(PPARγ),23,58 resulting in enhanced mitochondrial
function by stimulating mito­chondrial biogenesis and
increasing mitochondrial complex I activity.23 Decanoic
acid is a recognised PPARγ agonist, which elicits
neuronal mitochondrial biogenesis (figure 3).59–61 Similar
results have been shown in an in-vivo model,46 in which
rats given a diet including decanoic acid-containing
triglycerides had increased brain mitochondrial function
and ATP synthesis capacity. Additionally, one study in
mice62 confirmed a synergistic effect of PPARγ agonists
with the ketogenic diet in an in-vivo model of seizures.
This mechanism of increased brain mitochondrial
function seems to be specific to decanoic acid and is
unlikely to be shared by octanoic acid, the other major
component of the MCT ketogenic diet. In studies using
animal or human-derived cell lines, octanoic acid does
not activate PPARγ59 or enhance levels of mitochondria
in vitro,23 and octanoic acid-containing triglycerides do
not enhance mitochondria function in vivo.46 Additionally,
 Review

between medium-chain fatty acids and ketones, and the

Decanoic
acid
PPARγ PPARy activation
Decanoic
acid
RXR
PPA
Rγ
Enhanced gene expression
Mitochondrial biogenesis
Complex I
TCA cycle Increased mitochondrial function
ATP Optimum ATP availability
Figure 3: Schematic representation of stimulating mitochondrial biogenesis
with decanoic acid
Decanoic acid binds PPARγ; this complex (with the retinoid X receptor [RXR])
can then bind target DNA to elevate gene transcription and enhance gene
expression, which is thought to trigger mitochondrial biogenesis. Increasing the
amount of mitochondria in a cell leads to elevated activity of the tricarboxylic
acid (TCA) cycle and complex I (a component of the electron transport chain in
mitochondria), resulting in increased ATP availability. PPARγ=peroxisome
proliferator-activated receptor γ.
decanoic acid does not affect glycolytic enzymes,
suggesting limited contribution to its anticonvulsant
properties.46 These studies indicate that, in the MCT
ketogenic diet, decanoic acid rather than octanoic acid
might have a role in seizure control.
Although these direct and indirect mechanisms
identified in animal models have yet to be explored in
human beings, their identification is likely to trigger an
increasing interest in fatty acids as a therapeutic
mechanism of the ketogenic diet. As such, plasma fatty
acid concentrations (especially medium-chain fatty acids)
are likely to be monitored in future clinical MCT
ketogenic diet studies. Further research will also be
needed to examine the complex interactions in the brain
role of both components in seizure control.
The medium-chain triglyceride ketogenic diet
and other diseases
In addition to its use as a treatment for drug-resistant
epilepsy, the MCT ketogenic diet is increasingly being
considered as a potential treatment for a range of other
indications.
Alzheimer’s disease
The effect of ketones on metabolic activity in the brain5,6
highlights the potential of the ketogenic diet as a
treatment for metabolic changes underlying Alzheimer’s
disease. Reduced uptake and metabolism of glucose have
been strongly linked to progressive cognitive and motor
degeneration, as neurons starve because of inefficient
glycolysis.7 One study in rats63 has shown that the direct
application of the ketone β-hydroxybutyrate in relevant
concentrations protects hippocampal neurons from
amyloid-β toxicity. In another study,64 20 patients with
Alzheimer’s disease or mild cognitive impairment
received a single oral dose of MCT, but only patients
without the APOE ε4 allele showed enhanced short-term
cognitive performance, indicating that APOE ε4 genotype
might affect response to dietary treatments. Additionally,
three studies65–67 (including two randomised controlled
trials) have reported that treatment with an MCT
ketogenic diet benefited only patients with mild
Alzheimer’s disease who did not have an
APOE ε4 allele that was associated with Alzheimer’s
disease. Furthermore, in a transgenic mouse model of
amyloid deposition, both classic and MCT ketogenic
diets improved motor function but not cognition.68
Strong evidence exists that amyloid β increases
AMPA-receptor currents and triggers subunit
internalisation; this evidence directly links glutamate
receptor hyperactivity to neurotoxicity and memory loss
in Alzheimer’s disease. In rodent models, amyloid β has
been shown to interact with β-adrenergic receptors,
which regulate gene expression and the activity of other
receptors, including AMPA-type glutamate receptors via
the cAMP–protein kinase A signalling cascade.69,70
Phosphorylation of AMPA-receptor GluA1 subunits by
protein kinase A has been shown to increase channel
opening probability in human tissue culture, resulting in
augmented calcium entry into the cell, which can lead to
neurotoxicity.71 A study in rats72 has shown that the
addition of amyloid β to neuronal cultures causes
neurotoxicity by strengthening calcium-dependent
AMPA-receptor generated currents. This finding suggests
that amyloid-β-induced excitotoxicity could contribute to
the widespread neuronal death seen in Alzheimer’s
disease. In addition to ketones providing energy to
glucose-resistant neurons, the MCT ketogenic diet might
also improve neuronal survival through the inhibition of
AMPA receptors by decanoic acid. There is evidence in

88 www.thelancet.com/neurology Vol 17 January 2018


mice that amyloid β triggers the internalisation of GluA2
subunits, the only AMPA-receptor subunit type that
confers calcium impermeability.73,74 Internalisation of
GluA2 could therefore further increase total postsynaptic
calcium influx, which could further increase inflam­
mation and neurotoxicity. In rats, amyloid β-induced
internalisation of AMPA-receptor subunits has been
suggested to be sufficient to reduce long-term potentiation
and therefore be linked to memory loss in Alzheimer’s
disease.75 A study76 in patients has shown that loss of
GluA2 precedes pathological marker (tangles)
development in the brain. This effect would be augmented
if the remaining postsynaptic subunits were blocked by
AMPA-receptor antagonists. Further research is needed
to determine a role for the MCT ketogenic diet and
AMPA-receptor antagonists in the treatment of
Alzheimer’s disease.
Mitochondrial dysfunction has also been implicated in
the pathogenesis of Alzheimer’s disease. Structural
abnormalities of mitochondria, imbalances in mito­
chondrial fission and fusion, and defective electron
transport chain activity have been reported in a model of
Alzheimer’s disease.77 Moreover, evidence in mice
suggests that amyloid β accumulation is associated with
toxic effects in mitochondria, including impaired energy
homoeostasis and impaired electron transport chain
complex activity, particularly of cytochrome c oxidase
(also known as complex IV);77 disrupted mitochondrial
structure and dynamics;78 and increased mitochondrial
oxidative stress.77,79 With mitochondria intrinsically linked
to cell signalling, mitochondrial damage consequentially
leads to cell death and might cause the synaptic
degeneration seen in Alzheimer’s disease. However, very
few studies have investigated the therapeutic effects of
the MCT ketogenic diet in light of mitochondrial
function, although one in-vitro study80 has reported the
attenuation of deleterious amyloid β-induced effects on
rat cortical neurons treated with coconut oil (containing
high concentrations of MCT), observing increased cell
survival and improved mitochondrial structure and size.
Although the mechan­ isms of these observed effects
remain unknown, there remains a potential for the role
of medium-chain fatty acids in this context. In particular,
decanoic acid, which has the ability to improve
mitochondrial function (figure 3),23,81 might prove
beneficial in the amelioration of amyloid β-induced
mitochondrial damage. Additionally, the role of decanoic
acid as an antioxidant23,82 and as a PPARγ activator83
might provide insight into the molecular mechanisms
underlying the observed im­provement in mitochondrial
function.
Cancer
Ketogenic diets have gained substantial interest as an
adjunctive therapy in the treatment of cancer, with data
available from animal models8 and observational studies
in patients;9–12 however, evidence for clinical efficacy from
www.thelancet.com/neurology Vol 17 January 2018 89
Review
randomised controlled trials is scarce. Cancer cells are
often highly dependent on glucose as a substrate, relying
on anaerobic glycolysis to provide ATP, known as the
Warburg effect;84 this dependence on glucose is exploited
in tumour imaging, in which PET is used to measure
uptake of fluorodeoxyglucose. The commonly accepted
mechanism by which the ketogenic diet might aid in
cancer therapy is that the decrease in circulating blood
glucose, and the inability of tumours to use ketone bodies,
result in reduced tumour growth or tumour regression.85,86
Although this hypothesis remains the most accepted
explanation for a mechanism of the ketogenic diet, several
studies in animals and human-derived cell cultures9,12,87
have suggested that the effect on tumour growth might
not be solely caused by a decrease in blood glucose
concentrations. Many tumours preferentially use
glutamine as a substrate rather than glucose, but whether
a ketogenic diet has any effect on such tumours is
unknown and requires further investigation.
A link between the MCT ketogenic diet, AMPA recep­
tors, and cancer treatment comes from studies showing
that human glioblastoma cells express increased levels of
AMPA receptors88 and that inhibition of AMPA receptors
suppresses migration and proliferation of glioblastoma
multiforme cells89 and other cancer cells.90 Furthermore,
the AMPA receptor-specific inhibitor perampanel, which
binds at a different site to decanoic acid (figure 2),18 has
been shown to be a potentially chemotherapeutically
active adjuvant in a single case study of glioblastoma
multiforme cells treatment.91 These studies suggest that
AMPA-receptor inhibition with decanoic acid might
provide an adjunctive cancer treatment.
Diabetes
Diabetes can be broadly split into type 1 diabetes, in
which the pancreas does not produce enough insulin
because of a combination of genetic and environmental
factors, and type 2 diabetes, in which lifestyle choices
including obesogenic diets rich in carbohydrates and
saturated fats, together with insufficient exercise, lead to
hyperglycaemia and insulin resistance.92 Dietary
interventions, including the MCT ketogenic diet, have
been investigated as new therapeutic approaches, mainly
in type 2 diabetes. In several studies, MCT ketogenic
diets have been found to reduce serum lipid concen­
trations and improve lipid profiles, decrease body fat,
and reduce total bodyweight in animals13 and human
beings,14 and increase energy expenditure in human
beings.93 MCTs have also been shown to reduce insulin
resistance and improve glucose tolerance in an animal
model13 and in patients with type 2 diabetes.94 Although
the exact mechanism of these effects remains unknown,
these studies suggest a beneficial role of MCTs in the
treatment of type 2 diabetes and associated glucose-
sensitive metabolic disorders. Ketogenic diets in patients
with type 1 diabetes are more restricted in their benefit
than in patients with type 2 diabetes, with the scientific
 Review

Study description Intervention(s) Study population Location of lead Expected date of

centre completion*
NCT03075514 KDs as an adjuvant therapy in glioblastoma: a randomised pilot trial Modified KD vs MCT KD Glioblastoma UK March, 2018
NCT02825745 Use of Betashot in children and adults with epilepsy MCT-based emulsion Epilepsy UK December, 2017
NCT02516501 Impact of a KD intervention during radiotherapy on body MCT-based emulsion Neoplasms Germany June, 2018
composition
NCT02021526 Triheptanoin (C7 Oil), a food supplement, for glucose transporter Normal diet plus C7 oil vs Glucose transporter type I USA June, 2019
type I deficiency C7 oil as part of KD deficiency
NCT02426047 Medium-chain triglycerides as an adjunct to the modified Atkins diet Modified Atkins diet plus Epilepsy USA March, 2018
for women with catamenial epilepsy MCT-based emulsion
NCT02912936 A medium-chain triglyceride intervention for patients with MCT in milk vs sunflower Alzheimer’s disease Canada February, 2018
Alzheimer’s disease oil in milk
NCT02679222 Comparing the KD of coconut oil and different medium-chain Different MCT supplements Healthy adults Canada December, 2016
triglycerides
NCT02709356 Medium-chain triglycerides and brain metabolism in Alzheimer’s Different MCT emulsions Alzheimer’s disease and Canada July, 2017
disease healthy elderly people
NCT02409927 Effect of medium-chain triglyceride emulsification on ketogenesis in Different MCT preparations Healthy adults Canada September, 2014
adults
NCT02551419 Proof of mechanism of a new ketogenic supplement using dual MCT in milk vs sunflower Adults with mild cognitive Canada June, 2018
tracer PET oil in milk impairment

KD=ketogenic diet. MCT=medium-chain triglyceride. *Final data collection date for primary outcome measure.

Table: Completed and ongoing clinical trials using medium-chain triglyceride ketogenic diets

effect in the treatment of diabetes. As such, increasing

Search strategy and selection criteria
We selected references by searching PubMed for manuscripts
published in English between Jan 1, 2010, and Sept 18, 2017,
using the term “ketogenic diet” or ”medium-chain
triglyceride” and assorted combinations of the following
terms: “epilepsy”, “seizures”, “antiepileptic drugs”,
“dementia”, “neurodegenerative disease”, “Alzheimer’s
disease”, “diabetes”, “cancer”, and “tumour”. We examined
the reference lists within original research and review articles
for additional references. We finalised the reference list on the
basis of originality and relevance to the scope of this Review.
literature consisting of case reports of patients with
type 1 diabetes and poorly controlled epilepsy, or
anecdotal reports.95 A major concern about
implementation of any ketogenic diet in patients with
diabetes, especially type 1, is the potentially life-
threatening complication of diabetic ketoacidosis,
because low insulin promotes fatty acid oxidation and
ketosis.
Mitochondrial dysfunction has also been postulated to
have a role in insulin resistance and, consequently, the
pathology of diabetes. Patients with type 2 diabetes have
been found to have impaired mitochondrial activity,96
with alterations in function and morphology,97 in addition
to increased reactive oxygen species levels,98 which is
linked to insulin resistance. Genetic variations and
alterations in gene expression of PPARγ coactivator-1,99
the key regulator of mitochondrial biogenesis, have also
been proposed to have a role in the pathogenesis of
diabetes. In view of these findings, a role for decanoic
acid as a PPARγ agonist might provide a therapeutic
mitochondrial biogenesis through decanoic acid
treatment, in conjunction with improved mito­chondrial
function and increased antioxidant capacity, could form
a vital defence against the deleterious effects of
mitochondrial dysfunction in diabetes.
Conclusions and future directions
The MCT ketogenic diet is widely thought to function
through the generation of ketones, which provide an
alternative energy source for brain cells, and is considered
a potential treatment for a range of disorders including
epilepsy, Alzheimer’s disease, cancer, and diabetes.
However, the underlying mechanisms of the diet are still
largely unknown. Understanding the role of AMPA
receptors, PPARγ, and mitochondrial biosynthesis in
relation to MCT ketogenic diet-responsive disorders
might provide new therapeutic targets and facilitate the
development of new pharmacological and dietary
treatments (eg, different fatty acid content in MCT diets)
or chemical modification of fats to reduce metabolism
clearance. The pro­posed mechanism of AMPA-receptor
inhibition, PPARγ activation, and mitochondrial
biosynthesis provides a rationale for efficacy in other
conditions, and several clinical studies are currently
validating the use of the MCT ketogenic diet in the
treatment of other disorders (table). Additionally, further
clinical studies are needed to either decrease or mitigate
potential adverse effects of ketogenic diets, such as the
low-grade acidosis resulting from elevation in
β-hydroxybutyric and acetoacetic acids.100 Furthermore,
whether other ketogenic diets, such as the classic diet,
are also associated with elevated concentrations of
medium-chain fatty acids remains to be elucidated, and

90 www.thelancet.com/neurology Vol 17 January 2018


monitoring of these components in clinical studies will
help to investigate these mechanisms. Validation of these
fats provided in the diet as therapeutic targets might both
improve and widen the use of the diet as a treatment for
epilepsy, Alzheimer’s disease, cancer, diabetes, and other
disorders.
Contributors
All authors contributed equally to the preparation and writing of the
manuscript. All authors approved the final version.
Declaration of interests
MCW, RSBW, SJRH, SE, and JHC have received research funding from
Vitaflo. JHC has received grants from Zogenix and GW Pharmaceuticals,
and consultancy and speakers’ fees from Eisai, Shire, Zogenix, Nutricia,
UCB, and Takeda. MCW has received consultancy and speakers’ fees
from UCB and Eisai. RSBW has received speakers’ fees from UCB and
grants from GW pharmaceuticals. MCW and RSBW hold a patent (WO
2012069790) related to this Review, and SJRH, JHC, and SE hold a
further patent (WO 2013186570) related to this Review. KA and AK
received financial support from Vitaflo. SE received financial support
from Great Ormond Street Children’s Charity. SE, SJRH, and JHC
gratefully acknowledge financial support from the National Institute for
Health Research, Biomedical Research Centre at Great Ormond Street
Children’s Hospital. MO and SW declare no competing interests.
Acknowledgments
RSBW and MCW received support from NC3Rs (G0900775). KA was
supported by Vitaflo. SW was supported by the Medical Research
Council. MCW is also supported by University College London
Hospitals/University College London, which receives a proportion of
funding from the Department of Health’s National Institute for Health
Research, Biomedical Research Centres funding scheme.
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